Hydrazones of pyrazolo{8 3,4-b{9 pyridines

ABSTRACT

New hydrazones of pyrazolo(3,4-b)pyridines have the general formula:   They are useful as anti-inflammatory agents. In addition, this type of compound increases the intra-cellular concentration of adenosine-3&#39;&#39;,5-cyclic monophosphate.

mite States atent Hoehn et all.

[451 Jell 1975 HYDRAZONES 0F IP IRAZOLO[3,4-B]PYR1D1NES [75] Inventors:Hans Hoehn, Tegernheim; Ernst Schulze, Regensburg, both of Germany [73]Assignee: E. R. Squibb & Sons line,

Princeton, NJ.

[22] Filed: May 2 1, 197 1 [21] App]. No.: 473,122

[52] US. C1... 260/240 G; 260/296 1-1; 260/295.5 B

Primary Examiner-A1len E. Curtis Attorney, Agent, or Firm-Lawrence SLevinson; Merle J. Smith [57] ABSTRACT New hydrazones ofpyrazo1o[3,4-b]pyridines have the general formula:

They are useful as anti-inflammatory agents. In addition, this type ofcompound increases the intra-cellular concentration ofadenosine-3,5-cyclic monophosphate.

12 Claims, No Drawings 1 HYDRAZDNES F PYRAZDLO[3.4-b]PYRIDINES SUMMARYOF THE INVENTION This invention is related to new hydrazones ofpyrazolo[3,4-b]pyridines which have the general formula The symbols havethe following meanings in formula I and throughout this specification.

R is lower alkyl or phenyl-lower alkyl.

R is hydrogen or lower alkyl.

R is lower alkyl, phenyl or substituted phenyl and R is hydrogen orlower alkyl, phenyl or substituted phenyl, or R and R together completea C to C cycloaliphatic ring including cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl rings.

R is hydrogen, lower alkyl or phenyl.

The phenyl substituents in the substituted phenyl groups are halogen,lower alkyl or carboxy.

The lower alkyl groups are all straight or branched chain hydrocarbonsgroup of up to seven carbon atoms, preferably C C alkyl and especiallymethyl and ethyl.

Preferred are those compounds wherein R is lower alkyl, especiallyethyl, R is hydrogen or lower alkyl, especially methyl or ethyl, R ishydrogen or lower alkyl, especially methyl or propyl; R is lower alkyl,especially methyl or propyl, or phenyl; and R is hydrogen, methyl orphenyl, especially hydrogen.

DETAILED DESCRIPTION OF THE INVENTION The new compounds of formula I areformed by the following series of reactions. The symbols in thestructural formulas have the same meanings as previously described.

A S-aminopyrazole of the formula [prepared according to the proceduredescribed in Z. f. Chemie 10, 386388 (1970)] is made to react with anacyl acetic acid ester of the formula:

by heating at a temperature of about to C. in the presence ofpolyphosphorous acid producing a compound of the formula (IV) OHSubsequently, this 4-hydroxy compound of formula IV is refluxed forseveral hours with a phosphorous halide like phosphorous oxychloride toyield the intermediate of the formula hal Reaction of the halogenatedcompound of formula V with hydrazine leads to the compound of theformula l 2 I; A

JQt

l R R The hydrazones of formula I are then produced from the compoundsof formula VI with the appropriate aldehyde or ketone of the formula(v11) 0 ll (VIII) NH-N=C COOR droxide, and the saponified ester (R=H) isheated to about 200 to 240 with or without a solvent. This oper-- ationresults in decarboxylation and yields the hydrazone of formula 1 Thecompounds of formula I form salts which are also part of this invention.The salts include acid addition salts, particularly the non-toxic,physiologically acceptable members. The bases of formula I form salts byreaction with a variety of inorganic acids providing acid addition saltsincluding, for example, hydrohalides (especially hydrochloride andhydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate,malate, citrate, acetate, ascorbate, succinate, benzenesulfonate,methanesulfonate, cyclohexanesulfamate and toluenesulfonate. The acidaddition salts frequently provide a convenient means for isolating theproduct, e.g., by forming and precipitating the salt in an appropriatemenstruum in which the salt is insoluble, then after separation of thesalt, neutralizing with a base such as barium hydroxide or sodiumhydroxide, to obtain the free base of formula 1. Other salts may then beformed from the free base by reaction with an equivalent of acid.

The new compounds of this invention have antiinflammatory properties andare useful as antiinflammatory agents, for example, to reduce localinflammatory conditions such as those of an edematous nature orresulting from proliferation of connective tissue in various mammalianspecies such as rats, dogs and the like when given orally in dosages ofabout 5 to 50 mg/kg/day, preferably 5 to 25 mg/kg/day, in single or 2 to4 divided doses, as indicated by the carageenan edema assay in rats. Theactive substance may be utilized in compositions, such as tablets,capsules, solutions or suspensions containing up to about 200mg per unitof dosage of a compound or mixture of compounds of formula I orphysiologically acceptable acid addition salt thereof. They may becompounded in conventional manner with a physiologically acceptablevehicle or carrier, excipient, binder, preservative, stabilizer, flavor,etc. as called for by accepted pharmaceutical practice. Topicalpreparations containing about 0.01 to 3 percent by weight of activesubstance in a lotion, salve or cream may also be used. J

The new compounds also increase'the intracellular concentration ofadenosine-3',5-cyclic monophosphate, and thus by the administration ofabout 1 to 100 mg/kg/day, preferably about to 50 mg/kg, in single or twoto four divided doses in conventional oral or parenteral dosage formssuch as those described above may be used to alleviate the symptoms ofasthma.

The following examples are illustrative of the invention and constituteespecially preferred embodiments.

Othermembersof the group are prepared in similar manner by appropriatesubstitution of the reactants.

(1 EXAMPLE 1 -Etliy1-3-methylphenyl-4-[2-benzy1idene-)hydrazino]-1H-pyrazo1o[3 ,4-b ]pyridine a.l-Ethyl-4-hydroxy-3-methyl-6-phenyl-1H- pyrazolo[3,4-b]pyridine 96 g. ofbenzoylacetic acid ethyl ester (0.5 mol.) are added dropwise to astirred mixture of 62.5 g. of 5- amino-1-ethyl-3-methylpyrazole (0.5mol.) and 250 g. of polyphosphorous acid and heated to 130C. After thereaction has occurred which can be recognized by the changing of thecolor, the whole is heated for half an hour at 130C. After the mixturehas cooled to room temperature, 600 ml. of water are added and stirringis continued until the compound becomes crystalline. The collectedl-ethyl-4-hydroxy-3-methyl-6-pheny1- 1H-pyrazolo[ 3,4-b]pyridine istreated with dilute aqueous ammonia, washed with water, alcohol andether; yield=75.8 g. (60%), m.p. 251.5 -253.5C, (abs. ethanol).

b. 4-Ch1oro-1-ethyl-3-methyl-6-phenyl-1H- pyrazo1o[3,4-b]pyridine 147.5g. of 1-ethyl-4-hydroxy-3-methyl-6-phenyl-1H- -pyrazolo[3,4-b]pyridine(0.58 mol.) are. refluxed in 1000 ml. of phosphorous oxychloride for 6hours. The excess phosphorous oxychloride is removed in vacuo and theoily residue is treated with icewater by which operation the compoundbecomes solid. The 4-ch1oro- 1-ethyl-3-methy1-6-pheny1-1H-pyrazolo[3,4-b pyridine is extracted with ether, washed with aqueous, sodiumcarbonate ,solution (10%) and again with water. The ether extract isdried over sodium sulfate and treated with charcoal yielding 152.5 g.(96%) of the product; m.p. 778-80C. (cyclohexane).

pyrazolo[3,4-b1pyridine 54.3 g. of4-chloro-1-ethy1-3-methyl-6-phenyl-1H- pyrazolo[-3,4-b]pyridine (0.2mol.) are added to 20 g. of hydrazine hydrate (0.4 mol.) and the wholeis, heated at l200C. in an autoclave for 21 hours. After cooling, thesolution is evaporated in vacuo and the res idue is treated with waterand then extracted with ether. The ether extract is dried (Na SO andtreated with charcoal giving after evaporation a brown product,1-ethyl-4-hydrazino-3-methyl-6-pheny1-1 H- pyrazo1o[3.4-b]pyridine,which is recrystallized from cyclohexane, yield: 24.7 g. (46.3%); m.p.154.5156.5C.

d. 1-Ethyl-3-methyl-6-phenyl-4-[2- (benzylidene)hydrazino]-1H-pyrazo1o[3,4-b pyridine To 15 g. of 1-ethyl-4-hydrazino-3-methy1-6-phenyl-1H-pyrazolo[3,4-b]pyridine (0.056 mol.) dissolved in 500 ml. of absoluteethanol, 6.5 g. of benzaldehyde (0.056 mol.) are added and the whole isrefluxed for two hours. While heating the hydrazone begins toprecipitate, which increases in amount on cooling. After standingovernight, the I 1 -ethyl-3-methyl- 6-pheny1-4-[2-benzylidenehydrazino1-1 H- pyrazolo[3,4-b]pyridine is filtered off. With the quantity obtainedfrom the mother liquor, the yield amounts to 19.8 g. (99.5%); m.p.213214C. (absolute ethanol).

a. 1-Ethyl-4-[ 2-(4-chlorobenzylidene)hydrazino]- 11-Ethyl-4-hydrazino-3-methyl-6-phenyl-1H1l-l-pyrazolo[3.4-b]pyridine-5-carboxylic acid ethyl ester 24.9 g. ofl-ethyl-4-hydrazino-ll-l-pyrazolo[3,4- blpyridine-S-carboxylic acidethyl ester (0.1 mol.), prepared according to J. Heterocycl. Chemie 9,235 (1972), and 15.5 g. of p-chlorobenzaldehyde (0.11 mol.) dissolved in300 ml. of absolute ethanol are refluxed for 3 hours. Upon cooling, thehydrazone begins to crystallize. The mixture, after having been allowedto stand overnight, is filtered off. The dried l-ethyl-4-[2-(4-chlorobenzylidene)hydrazino]- l H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester amounts to 34.8 g.(93.5%); m.p. l66l67C. (absolute ethanol).

b. 1Ethyl- H2-(4-chlorobenzylidene)hydrazino]-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid A suspension of 30 g. ofl-ethy]-4[2-(4- chlorobenzylidene)hydrazino]- 1 l-ll-pyrazolo[ 3,4-b]pyridine-5-carboxylic acid ethyl ester (0.081 mol.) in 500 ml. ofaqueous sodium hydroxide (32 g/l) and 600 ml. of ethanol is stirred at80 until the ester has dissolved. After removal of ethanol, the clearsolution is acidified with diluted aqueous acetic acid (25%) to yield27.4 g. (97%) ofl-ethyl-4-[2-(4-chlorobenzyllidene)hydrazino]-1li-ll-pyrazolol3,4-b]pyridine-5-carboxylicacid that, after recrystallization from dioxane, melts at 229231C.(dec.).

c. 1Ethyl-4-[ 2-( 4-chlorobenzylidene)hydrazino]- 1l-l-pyrazolo[3,4-b]pyridine 17 g. of chlorobenzylidene)hydrazino]1l-l-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.05 mol.) suspended in300 ml. of nitrobenzene, are heated at 2002lOC. (bath temperature) for 2hours. After removal of the nitrobenzene, the residue is treated withether and the l-ethyl-4-2-(4-chlorobenzy1idene)hydrazinol-1l'r-l-pyrazolo[3,4- b]pyridine isfiltered off yielding g. (67%); m.p. 242243C. (acetonitrile).

EXAMPLE 3 1 -Ethy1-4-[2-(isopropylidene)hydrazino]-3-methylllHl-pyrazolo 3 ,4-b]pyridine a.l-Ethyl-4-[2-(isopropylidene)hydrazino]-3- methyl- 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid 21.6 g. ofl-ethyl-4-[2-(isopropylidene)hydrazino]-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester [(1.Heterocycl. Chemie 9, 235 (1972)] suspended in a solution of 400 ml. ofethanol and 500 ml. of aqueous sodium hydroxide (28.4 g/l) is stirred atroom temperature until the ester is dissolved (about 45 hours). Afterremoval of the ethanol in vacuo, the clear solution is acidified withdilute aqueous acetic acid separating the crystalline l-ethyl-4-[2-(isopropylidene)hydrazinol-3-methyll l-l-pyrazolo[ 3,44)]pyridine-5-carboxylic acid, yield 18.3 g. (94%); m.p. 2l8219C. (dec.)(ethanol).

b. l-Ethyl-4-[2-(isopropylidene)hydrazino]-3- methyl- 1 l-l-pyrazolo 3,4-b]pyridine 18.3 g. of l-ethyl-4-[2-(isopropylidene)hydrazino]-3-methyl-1l-l-pyrazolol3,4-b]pyridine-5-carboxylic acid are heated at220C. (bath temperature) for minutes. After cooling, the solidl-ethyl-4-[2- 6 (isopropylidene )hydrazino -3-methyll H-pyrazolo[3,4-b]pyridine (l4 g.=92%) is recrystallized from ethylacetate, m.p. 141.5142.5 C.

EXAMPLE 4 1-Ethyl-3-methyl-4-[2-(benzylidene)hydrazino]- l H- pyrazolo 3,4-b pyridine l-Ethyl-3-methyl-4-[2-(benzylidene)hydrazino]- 1 H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester [(m.p. 161l62C),prepared according to J. Heterocycl. Chemie 9, 235 (1972)], issaponified with sodium hydroxide as in Example 3a to give1-ethyl-3-methyl-4- [2-(benzylidene)hydrazino]-1H- pyrazolo[ 3,4-b]pyridine-5-carboxylic acid, m.p. l99201C. (dioxane).Decarboxylation of the acid at 230 (bath temperature) givesl-ethyl-3-methyl-4-[2-(benzylidene)hydrazino]-1ll-l-pyrazolo[3,4-b]pyridine which is dissolvedin ether. Addition of ethereal hydrochloride acid separates thehydrochloride, m.p. 275-277 (absolute ethanol); yield 83%.

The following additional products are made by the procedure of Example3.

The following additional products are obtained by decarboxylatingaccording to the procedure of Example 4 the carboxylic acid ester(produced as described in US. Pat. No. 3,773,777):

EXAMPLE 9 4-[2-(benzylidene)hydrazino]-l-ethyl-1li-lpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester(m.p.225-226) is decarboxylated to yield 4-[2- benzylidene )hydrazino]-l -ethyl- 1l-l-pyrazolo-[ 3,4-b pyridine.

EXAMPLE 10 4--[ 2-(isopropylidene)hydrazino]- 1 -methyl- 1 H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester is decarboxylatedto yield 4-[2- (isopropylidene)hydrazino]- 1 -methylll-l-pyrazolo[ 3,4-b]pyridine.

EXAMPLE 1 l 1-isopropyl-4-[2-(isopropylidene )hydrazino 1 11-11- 7pyrazolo[3,4-b]pyridine--carboxylic acid, ethyl "ester is decarboxylatedto yield 'l-isopropyl-4-[2-(isopropylidene)hydrazino]-ll-lpyrazolo[3,4-b]pyridine.

EXAMPLE 12l-ethyl-4-[2-(isopropylidene)hydiazino1-6-methyllH-pyrazolo[3,4-b]pyridine-5-carboxylicacid, ethyl ester is decarboxylated to yieldl-ethyl-4-[2-(isopropylidene)hydrazino]- 6-methyll H-pyrazolo[ 3,4-b]pyridine.

EXAMPLE l3 l -ethyl-4-[ 2-( isopropylidene)hydrazirio1-6-phenylll-l-.pyra zolo[ 3 ,4-blpyridine-S-carboxylic acid,ethyl ester is decarboxylated to yield l-ethyl-4-[2-(isopropylidene)hydrazino 6-phenyl 1 H-pyrazolo[ 3 ,4-b ]pyridine.

EXAMPLE l4 EXAMPLE l5 acetaldehyde for benzaldehyde in part d.

EXAMPLE 16 l ,3-diethyl-6-phenyl-4- 2-(benzylidene )hydrazino'll-l-pyrazolo[3,4-b]pyridineis obtained by the procedure of Example 1bysubstituting 5-amino-1,3-

diethylpyrazole for the S-aminol -ethyl-3- methylpyrazole in part a.

EXAMPLE 17 l-ethyl-4-[ 2-( ethylpropylidene )hydrazino1-3 ,6-dimethyl-ll-l-pyrazolo[3,4-b]pyridine is obtained by the procedure ofExample 2 by substituting diethyl ketone for the p-chlorobenzaldehyde.

EXAMPLE ,1 8

l-ethyl-4-[ 2-(cyclopropylidene )hydrazino l H- pyrazolo[3,4-b]pyridineis obtained by the procedure of Example 2 by substituting cyclopropanonefor the p-chlorobenzaldehyde.

EXAMPLE l9 l-ethyl'4[2-(cyclopentylidene)hydrazino]- l H-pyrazolo[3,4-b]pyridine is obtained by'the procedure of Example 2 bysubstituting cyclopentanone for the p-chlorobenzaldehyde.

EXAMPLE l -ethyl-4-[ 2-( 3-bromobenzylidene)hydraiino1-l H-pyrazolo[3,4-b]pyridine is obtained by the procedure g of Example 2 bysubstituting m-bromobenzaldehyde '8 for the p-chlorobenzaldehyde.

EXAMPLE 2] l-ethyl-4-[2-(2-methylbenzylidene)hydrazino]-1H-pyrazolo[3,4-b]pyridine is obtained by the procedure of Example 2 bysubstituting o-tolualdehyde for the P, chloroben'zaldehyde.

EXAMPLE 22 l-ethyl-4-[ 2-(2-carboxybenzylidene)hydrazino1- l H-pyrazolo[3,4-b]pyridine is obtained by the procedure of Example 2 bysubstituting o-carboxybenzaldehyde for the p-chlorobenzaldehyde.

What is claimed is:

1. A compound of the formula wherein R, is lower alkyl or phenyl-loweralkyl; R is hydrogen or lower alkyl, R, is lower alkyl, phenyl orsubstituted phenyl; R, is hydrogen, lower alkyl, phenyl or substitutedphenyl, said phenyl substituents being halogen, lower alkyl or carboxy;or R and R together complete a C to C cycloalkyl ring; and R ishydrogen, lower alkyl or phenyl; and physiologically acceptable acidaddition salts thereof.

2. A compound as in claim 1 wherein R, is lower alkyl; R and R, each ishydrogen or lower alkyl; R, is lower alkyl or phenyl; and R is hydrogen,methyl or phenyl.

3. A compound as in claim 1 wherein R,, R and R, each is lower alkyl andR and R each is hydrogen.

4. A compound as in claim 1 wherein R,, R R and R each is lower alkyland R is hydrogen.

5. A compound as in claim 1 wherein R, is lower alkyl, R R, and R eachis hydrogen and R is phenyl.

6. A compound as in claim 1 wherein R, and R each is lower alkyl, R, isphenyl and R, and R each is hydrogen.

7. A compound as in claim 1 wherein R, and R each is lower alkyl, R andR each is phenyl and R, is hydrogen.

I 8. A compound as in claim 1 wherein R, is ethyl, R is methyl, R and Reach is phenyl and R is hydrogen.

9. A compound as in claim 1 wherein R, is ethyl, R R and R each ishydrogen and R is p-chlorophenyl.

10. A compound as in claim 1 wherein R, is ethyl, R R and R each ismethyl and R is hydrogen.

1 A compound as in claim 1 wherein R, is ethyl, R is methyl, R is phenyland R and R each is hydrogen.

12. A compound as in claim 1 wherein R, is ethyl, R and R each ishydrogen and R and R, together with the carbon to which they areattached form a cyclohexyl ring.

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R1 islower alkyl; R2 and R3 each is hydrogen or lower alkyl; R4 is loweralkyl or phenyl; and R5 is hydrogen, methyl or phenyl.
 3. A compound asin claim 1 wherein R1, R3 and R4 each is lower alkyl and R2 and R5 eachis hydrogen.
 4. A compound as in claim 1 wherein R1, R2, R3 and R4 eachis lower alkyl and R5 is hydrogen.
 5. A compound as in claim 1 whereinR1 is lower alkyl, R2, R4 and R5 each is hydrogen and R3 is phenyl.
 6. Acompound as in claim 1 wherein R1 and R2 each is lower alkyl, R3 isphenyl and R4 and R5 each is hydrogen.
 7. A compound as in claim 1wherein R1 and R2 each is lower alkyl, R3 and R5 each is phenyl and R4is hydrogen.
 8. A compound as in claim 1 wherein R1 is ethyl, R2 ismethyl, R3 and R5 each is phenyl and R4 is hydrogen.
 9. A compound as inclaim 1 wherein R1 is ethyl, R2, R4 and R5 each is hydrogen and R3 isp-chlorophenyl.
 10. A compound as in claim 1 wherein R1 is ethyl, R2, R3and R4 each is methyl and R5 is hydrogen.
 11. A compound as in claim 1wherein R1 is ethyl, R2 is methyl, R3 is phenyl and R4 and R5 each ishydrogen.
 12. A compound as in claim 1 wherein R1 is ethyl, R2 and R5each is hydrogen and R3 and R4 together with the carbon to which theyare attached form a cyclohexyl ring.